Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment
Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment
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DOI：
10.1038/ncb3387
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发表时间：
2016-08-01
影响因子：
21.3
通讯作者：
Wickstroem, Sara A.
中科院分区：
文献类型：
--
作者：
Huy Quang Le;Ghatak, Sushmita;Wickstroem, Sara A.
组织力学驱动形态发生，但力量如何被感知和传递以控制干细胞的命运和自我组织仍不清楚。我们表明，Emd、非肌肉肌球蛋白IIA（NMIIA）和肌动蛋白的机械感觉复合物控制基因沉默和染色质致密化，从而调节谱系定型。在表皮干细胞的外核膜处的Emd的力驱动富集导致有缺陷的异染色质锚定到核层，并且在组成性异染色质处从H3K9me2，3切换到H3K27me3占据。Emd富集伴随着NMIIA的募集以促进局部肌动蛋白聚合，从而降低核肌动蛋白水平，导致转录减弱和随后H3K27me3在兼性异染色质处的积累。通过删除小鼠表皮中的NMIIA来扰乱该机械感觉通路导致减弱的H3K27me3介导的沉默和早熟谱系定型，从而废除形态发生。我们的研究结果揭示了力学如何整合核结构和染色质组织控制谱系承诺和组织形态发生。
Tissue mechanics drive morphogenesis, but how forces are sensed and transmitted to control stem cell fate and self-organization remains unclear. We show that a mechanosensory complex of emerin (Emd), non-muscle myosin IIA (NMIIA) and actin controls gene silencing and chromatin compaction, thereby regulating lineage commitment. Force-driven enrichment of Emd at the outer nuclear membrane of epidermal stem cells leads to defective heterochromatin anchoring to the nuclear lamina and a switch from H3K9me2,3 to H3K27me3 occupancy at constitutive heterochromatin. Emd enrichment is accompanied by the recruitment of NMIIA to promote local actin polymerization that reduces nuclear actin levels, resulting in attenuation of transcription and subsequent accumulation of H3K27me3 at facultative heterochromatin. Perturbing this mechanosensory pathway by deleting NMIIA in mouse epidermis leads to attenuated H3K27me3-mediated silencing and precocious lineage commitment, abrogating morphogenesis. Our results reveal how mechanics integrate nuclear architecture and chromatin organization to control lineage commitment and tissue morphogenesis.